Wolfram's Syndrome and Wolframin
Wolfram Syndrome (WFS) or DIDMOAD (MIM222300) is an autosomal recessive disorder most frequently characterized by Diabetes Insipidis, juvenile Diabetes Mellitus, bilateral Optic Atrophy and sensoneural Deafness (Strom et al., Hum. Mol. Genetics. 7(13) 2021, 1998). Minimally, individuals presenting this syndrome have diabetes mellitus and optic atrophy, however, diabetes insipidous sensorineuronal deafness, urinary tract atony, ataxia, peripheral neuropathy, mental retardation and psychiatric illness also are observed in the vast majority of patients. A range of psychiatric conditions also have been associated with WFS, including dementia, psychosis, affective disorder, major depressive disorder, suicide and assaultive behavior. (Owen, Mol. Psychiatry, 3, 12, 1998; Swift et al., Am. J. Psychiatry, 148, 775, 1991).
Recently, WFS was linked to markers on chromosome 4p. On the basis of meiotic recombinant and disease associated haplotypes, the WFS1 gene was identified as Wolframin (WFS1). This gene codes for a predicted transmembrane protein (Wolframin protein) which is expressed in a variety of tissues including the brain and pancreas. The human transmembrane protein was described in 1998 (Strom et al., supra and Inoue et al. Nature Genetics 20, 121, 1998). The 890 amino acid protein corresponds to a predicted molecular weight of 100 kDa.
Loss of function mutations in both alleles of this gene are associated with the disease characteristics of WFS (Inoue et al., supra; Strom et al., supra). While the homozygous loss of function mutations in the WFS1 gene have been associated with WFS, individuals that are blood relatives of individuals manifesting WFS have a 26 fold greater predisposition to psychiatric illness, including depression and depressive disorders, than those individuals that are not genetically related to individuals suffering with WFS. The odds ratio reported, 26, estimates the risk of psychiatric hospitalization (for paraonoid delusions, progressive dementia, attempted suicides, hallucinations and violent and assaultive behavior, but most notably for depression) for a Wolfram syndrome gene carrier compared to a non-carrier. Given this estimate and the estimate that Wofram syndrome heterozygotes are 1% of the population, carriers of the gene maybe constitute approximately 25% of all persons hospitalized with similar psychiatric difficulties. (Swift et al., Mol. Psychiatry, 3, 86–91, 1998).
Wolframin protein by virtue of the convincing genetic evidence presented above is associated with a variety of health problems including diabetes insipidis, diabetes mellitus, and depression. While treatment of all diseases associated with Wolframin protein dysfunction are problematic, the treatment of depression poses particular difficulties. Numerous compounds have been developed to treat depression including for example serotonin re-uptake inhibitors (SSRI), such as sertraline (registered trademark ZOLOFT, Pfizer), fluoxetine (PROZAC—Eli Lilly), paroxetine (PAXIL—Smith Kline Beecham) and fluvoxamine (LWOX); tricyclic antidepressants such as ELAVIL (Merck, Sharpe and Dohme), aminoketone antidepressants such as bupropion, and lithium, a metal used to treat bipolar disorder. However, these drugs are very potent, often generating problematic side effects such as lethargy, clouded thinking and a lack of ability to concentrate. A pressing need exists therefore for the identification of new molecular targets and assays employing those targets as methods of identifying compounds useful in the treatment of depression and other Wolframin protein associated diseases. The heretofore undisclosed assays detailed below address this need by providing for the assessment of small molecule modulators of the functional characteristics of the Wolframin protein.